EP0093564B1 - Beta-Lactam-Antibiotika - Google Patents

Beta-Lactam-Antibiotika Download PDF

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Publication number
EP0093564B1
EP0093564B1 EP83302349A EP83302349A EP0093564B1 EP 0093564 B1 EP0093564 B1 EP 0093564B1 EP 83302349 A EP83302349 A EP 83302349A EP 83302349 A EP83302349 A EP 83302349A EP 0093564 B1 EP0093564 B1 EP 0093564B1
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alkyl
compound
acid
group
formula
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EP0093564A1 (de
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Michael John Driver
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Beecham Group PLC
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Beecham Group PLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
    • C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01L—SEMICONDUCTOR DEVICES NOT COVERED BY CLASS H10
    • H01L21/00—Processes or apparatus adapted for the manufacture or treatment of semiconductor or solid state devices or of parts thereof
    • H01L21/02—Manufacture or treatment of semiconductor devices or of parts thereof
    • H01L21/027—Making masks on semiconductor bodies for further photolithographic processing not provided for in group H01L21/18 or H01L21/34
    • H01L21/0271—Making masks on semiconductor bodies for further photolithographic processing not provided for in group H01L21/18 or H01L21/34 comprising organic layers
    • H01L21/0273—Making masks on semiconductor bodies for further photolithographic processing not provided for in group H01L21/18 or H01L21/34 comprising organic layers characterised by the treatment of photoresist layers
    • H01L21/0274—Photolithographic processes
    • H01L21/0276—Photolithographic processes using an anti-reflective coating

Definitions

  • This invention relates to a class of penicillin derivatives which have antibacterial activity and are of value in the treatment of infections in animals, especially mammals, including man, caused by a wide range of organisms.
  • the invention relates to a class of bis nor penicillin derivatives.
  • the invention also relates to a process for the preparation of such compounds and to pharmaceutical compositions comprising them.
  • a compound of formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof wherein R is hydrogen or C 1-6 alkylcarbonyl; R 1 is hydrogen or C 1-6 alkyl; R 2 is hydrogen, C 1-6 alkyl optionally substituted by heterocyclyl, a heterocyclyl group, or CXR d where X is 0 or S and R is hydrogen, C 1-6 alkyl optionally substituted by heterocyclyl, or a heterocyclyl group; or R 1 and R 2 together with the nitrogen to which they are attached form a heterocyclyl group; the aforementioned heterocyclyl groups comprising single or fused rings having up to four hetero atoms in the ring selected from oxygen, nitrogen and sulphur and optionally substituted with up to three halogen, C 1-6 alkyl, C 1-6 alkoxy, halo-(C 1-6 )-alkyl, hydroxy, amino, carboxy, C 1-6 alkoxy
  • R is hydrogen or acetyl.
  • R is hydrogen
  • Suitable alkyl groups are straight and branched chain alkyl groups containing from 1 to 6 carbon atoms, such as methyl, ethyl, propyl and butyl.
  • a particular alkyl group is methyl.
  • R 2 is a group, CORd, or R 1 and R 2 together with the nitrogen atom to which they are attached form an optionally substituted five- or six-membered heterocyclic group containing one or two nitrogen atoms.
  • R d is hydrogen
  • esters which break down to give the parent acid include, for example acyloxyalkyl groups, such as acetoxymethyl, pivaloyloxymethyl, a-acetoxyethyl and a-pivaloyloxyethyl groups; alkoxycarbonyloxyalkyl groups, such as ethoxycarbonyloxymethyl and a-ethoxycarbonyloxyethyl; dialkylaminoalkyl groups, such as dimethylaminomethyl, dimethylaminoethyl, diethylaminoethyl or diethylaminoethyl; and lactone groups such as phthalidyl or dimethoxyphthalidyl.
  • acyloxyalkyl groups such as acetoxymethyl, pivaloyloxymethyl, a-acetoxyethyl and a-pivaloyloxyethyl groups
  • alkoxycarbonyloxyalkyl groups such as ethoxycarbonyloxy
  • the compounds of the present invention contain both an amino group and a carboxyl group and may, therefore, exist as the zwitterion or may form salts with suitable acids or bases.
  • Suitable pharmaceutically acceptable salts of the compounds of formula (I) include metal salts, eg aluminium, alkali metal salts such as sodium or potassium, alkaline earth metal salts such as calcium or magnesium and ammonium or substituted ammonium salts, for example those with lower alkylamines such as triethylamine, hydroxy-lower alkylamines such as 2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine or tri-(2-hydroxyethyl)-amine, cycloalkylamines such as bicyclohexylamine, or with procaine, dibenzylpiperidine, N-benzyl-p-phenethylamine, dehydroabrietylamine, N,N'-bisdehydroabietylamine, ethylenediamine, or bases of the pyridine type such as pyridine, collidine or quinoline.
  • metal salts eg aluminium, alkali metal salts such as sodium or potassium, alkaline
  • the carbon atom marked * in formula (I) is asymmetric and the compound may be derived from the side-chain having a D, L or DL configuration at that position. All forms of compound (I) are included in this invention.
  • the carbon atom marked * is derived from the D-configuration and is conveniently referred to as the D-bis nor penicillin.
  • One preferred sub-group within the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof: wherein R is as defined hereinbefore, R 3 represents hydrogen or C 1-6 alkyl; R 4 and R 5 are the same or different and represent hydrogen, C 1 - 6 alkyl, halogen, amino, hydroxy or C 1 - 6 alkoxy.
  • Suitable C 1 - 6 alkyl groups for the groups R 3 , R 4 and R 5 include methyl, ethyl, n- and iso-propyl, n-, sec-, iso- and tert-butyl.
  • R 3 is ethyl.
  • R 4 and R 5 are hydrogen.
  • the compounds of formula (I) may be prepared by reacting a compound of formula (III): wherein R is as hereinbefore defined, the a-amino group is optionally substituted with a group which permits acylation to take place, and R" is hydrogen or a carboxyl-blocking group, with an N-acylating derivative of an acid of formula (IV): wherein R 1 and R 2 are as defined with respect to formula (I) above and any reactive groups may be protected; and thereafter, if necessary, carrying out one or more of the following steps:
  • Suitable carboxyl-blocking derivatives for the group -C0 2 R' in formula (III) include salts and ester derivatives of the carboxylic acid.
  • the derivative is preferably one which may readily be cleaved at a later stage of the reaction.
  • Suitable salts include metal salts, such as those with sodium, potassium and lithium, and tertiary amine salts, such as those with tri-lower-alkylamines, N-ethylpiperidine, 2,6-lutidine, pyridine, N-methylpyrrolidine, dimethylpiperazine.
  • a preferred salt is with triethylamine.
  • the carboxyl group may be regenerated from any of the above esters by usual methods appropriate to the particular R" group, for example, acid - and base - catalysed hydrolysis, or by enzymically - catalysed hydrolysis, or by hydrogenation.
  • a reactive N-acylatihg derivative of the acid (IV) is employed in the above process.
  • the choice of reactive derivative will, of course, be influenced by the chemical nature of the substituents of the acid.
  • Suitable N-acylating derivatives include an acid halide, preferably the acid chloride or bromide.
  • Acylation with an acid halide may be affected in the presence of an acid binding agent for example, tertiary amine (such as triethylamine or dimethylaniline), an inorganic base (such as calcium carbonate or sodium bicarbonate) or an oxirane, which binds hydrogen halide liberated in the acylation reaction.
  • the oxirane is preferably a (C 1-6 )-1,2-alkylene oxide ⁇ such as ethylene oxide or propylene oxide.
  • reactive N-acylating derivatives of the acid (IV) include the reactive intermediate formed by reaction in situ with a condensing agent such as a carbodiimide, for example N,N-diethyl-, dipropyl-, or diisopropylcarbodiimide, N,N'-dicyclohexylcarbodiimide or N-ethyl-N'-y-dimethylaminopropylcarbo- diimide; a suitable carbonyl compound, for example N,N'-carbonyldiimidazole or N,N'-carbonylditriazole; an isoxasolinium salt, for example N-ethyl-5-phenylisoxazolinium-2-sulphonate or N-t-butyl-5-methyl- isoxazolinium perchlorate; or an N-alkoxycarbonyl-2-alkoxy-1,2-dihydroquinoline, such as N-ethoxycarbonyl-2-e
  • condensing agents include Lewis acids (for example BBr3-C 6 H 6 ); or a phosphoric acid condensing agent such as diethylphosphoryl-cyanide.
  • the condensation reaction is preferably carried out in an organic reaction medium, for example methylene chloride, dimethylformamide, acetonitrile, alcohol, benzene, dioxan, or tetrahydrofuran.
  • the compounds of formula (I) may also be prepared by reacting a compound of formula (V): wherein the amino group is optionally substituted with a group which permits acylation to take place and R" is as defined with respect to formula (III) above, with an N-acvlatinq derivative of an acid of formula (VI1: wherein R, R 1 and R are as defined with respect to formula (I) and any reactive groups therein may be protected; and thereafter, if necessary, carrying out one or more of the following steps:
  • Suitable amino-protecting groups R Y are those well-known in the art which may be removed under conventional conditions without disruption of the remainder of the molecule.
  • compositions may be formulated for administration by any route, such as oral topical or parenteral.
  • the compositions may be in the form of tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents.
  • suspending agents for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or
  • Suppositories will contain conventional suppository bases, e.g. cocoa-butter or other glyceride.
  • fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, water being preferred.
  • the compound depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
  • the compound can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
  • agents such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilized powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use.
  • Parental suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration.
  • the compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • compositions may contain from 0.1 % by weight, preferably from 10-60% by weight, of the active material, depending on the method of administration. Where the composition comprise dosage units, each unit will preferably contain from 50-500 mg of the active ingredient.
  • the dosage as employed for adult human treatment will preferably range from 100 - to 3000 mg per day, for instance 1500 mg per day depending on the route and frequency of administration.
  • the compound of formula (I) may be the sole therapeutic agent in the compositions of the invention or a combination with other antibiotics or with a (3-tactamase inhibitor may be employed.
  • compositions also comprise a compound of formula (VIII) or a pharmaceutically acceptable salt or ester thereof: wherein A is hydroxyl, substituted hydroxyl, thiol, substituted thiol, amino, mono- or di-hydrocarbyl- substituted amino, or mono- or di-acylamino.
  • a further advantageous composition comprises a compound of formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof together with a compound of formula (IX) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof:
  • the aqueous phase was basified to pH 7.5 and the organic phase then separated and discarded. Acidification of the aqueous solution to pH 1.5 with dilute hydrochloric acid followed by extraction with 10% n-butanol in ethyl acetate (3 x 50 ml), drying of the combined extracts (MgS0 4 ) and evaporation gave an off-white foam.
  • This product dissolved in acetone (10 ml) was dropped into diethyl ether (100 ml) with vigorous stirring to give the title compound as a solid (1.3 g, 27%) m.p.
  • Benzyl 6,6-aminobisnorpenicillanate (0.28 g, 1 mmol) in dry dichloromethane (10 ml) with dicyclohexylcarbodiimide (0.21 g, 1 mmol) at 0°C was treated with D-2(4-ethyl-2,3-dioxopiperazine-1-carboxylamino)-2-(3,4-diacetoxyphenyl)acetic acid (0.43 g, 1 mmol) in dry dichloromethane (10 ml). The mixture was allowed to warm to 21°C and stirred for 2.5 h when precipitated urea was removed by filtration.
  • the title compound was prepared employing an analogous sequence of reactions as described in Example 1 starting from DL-3,4-dihydroxyphenylglycine.
  • the acid (0.5 g, 1.4 mmol) from example 3(a) was partitioned between ethyl acetate and water at pH 6.5. The aqueous phase was separated and freeze-dried to give the sodium salt as a white amorphous solid which was dried over phosphorous pentoxide in vacuo (0.45 g, 85%).
  • N-Methylbenzamide (0.41 g, 3 mmol) with 4-N,N-dimethylaminopyridine (0.1 g, 0.8 mmol) in dry dichloromethane (4 ml) was treated with triethylamine (0.42 ml, 3 mmol) and then trimethylsilyl chloride (0.38 ml, 3 mmol) for 0.5 hours at 21°.
  • the solution was then heated under reflux for 0.5 hours, cooled, evaporated to ca 1 ml and diluted with dry dichloromethane (5 ml).
  • This ester was prepared from the reaction of D,2-[3-(4-chlorophenylcarbonyl)-3-methyl-1-ureido]-2-(3,4-dihydroxyphenyl)acetic acid (0.38 g, 1 mmol) and benzyl 6 ⁇ -aminobisnorpenicillanate (0.28 g, 1 mmol) using a method analogous to that described in example 5(b). The yield was 0.3 g, 47%.

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Claims (10)

1. Eine Verbindung der Formel (I) oder ein pharmazeutisch verträgliches Salz oder ein in-vivo hydrolysierbarer Ester davon:
Figure imgb0018
in welcher R Wasserstoff oder C1-6-Alkylcarbonyl, ist; R' Wasserstoff oder ein C1-6-Alkyl ist; R2 Wasserstoff, ein C1-6Alkyl, gegebenenfalls substituiert durch Heterocyclyl, eine heterocyclische Gruppe oder eine Gruppe CXRd, in welcher X Sauerstoff oder Schwefel bedeutet und Rd Wasserstoff, C1-6-Alkyl, gegebenenfalls substituiert durch Heterocyclyl, oder eine heterocyclische Gruppe bedeutet; oder R1 und R2 zusammen mit dem Stickstoffatom, an das sie gebunden sind, eine heterocyclische Gruppe bilden, wobei die vorstehend genannten heterocyclischen Gruppen einzelne oder miteinander kondensierte Ringe mit bis zu 4 Heteroatomen in der Ringstruktur enthalten, ausgewählt aus Sauerstoff, Stickstoff und Schwefel und welche gegebenenfalls substituiert sind, mit bis zu drei Gruppen ausgewählt aus Halogen, C1-6-Alkyl, C1-6Alkoxy, Halo-(C1-6)-alkyl, Hydroxy, Amino, Carboxy, C1-6-Alkoxycarbonyl, C1-6-Alkoxycarbonyl (C1-6)alkyl, Oxo oder Phenyl, letzteres gegebenenfalls substituiert mit bis zu drei Gruppen ausgewählt aus Halogen, C1-6-Alkyl, Phenyl, C1-6-Alkoxy, Halo(C1-6)alkyl, Hydroxy, Amino, Nitro, Carboxy, C1-6-Alkoxycarbonyl, C1-6-Alkoxycarbonyl(C1-6)alkyl, C1-6-Alkoxycarbonyloxy, oder C1-6-Alkylcarbonyl, oder Naphthyl, gegebenenfalls substituiert durch die für Phenyl aufgeführten Substituenten.
2. Eine Verbindung wie in Anspruch 1 beansprucht, in welcher R Wasserstoff oder Acetyl ist.
3. Eine Verbindung wie in einem der beiden Ansprüche 1 oder 2 beansprucht, in welcher R' Wasserstoff oder C1-6-Alkyl ist.
4. Eine Verbindung wie in Anspruch 3 beansprucht, in welcher R2 eine Gruppe CORd ist, wobei Rd wie in Anspruch 1 definiert ist.
5. Eine Verbindung der Formel (II) oder ein pharmazeutisch verträgliches Salz oder ein in-vivo hydrolysierbarer Ester derselben:
Figure imgb0019
in weicher R wie in Anspruch 1 definiert ist, R3 Wasserstoff oder C1-6-Alkyl bedeutet; R4 und R5 gleich oder verschieden sind und Wasserstoff, C1-6-Alkyl, Halogen, Amino, Hydroxy, Hydroxy oder C1-6-Alkoxy bedeuten.
6. 6β-[D-2-(4-Äthyl-2,3-dioxopiperazin-1-carbonylamino)-2-(3,4-dihydroxyphenyl)]acetamidobisnor- penicillansäure;
6β-[D,L-2-(4-Äthyl-2,3-dioxopiperazin-1-carbonylamino)-2-(3,4-dihydroxyphenyl)]acetamidobisnor- penicillansäure;
6,β-[D,L-2-[3-(3,4-Diacetoxyphenylcarbonyl)-3-methyl-1-ureido]-2-(3,4-diacetoxyphenyl)]ace- tamidobisnorpenicillan-säure;
6,β-[D,L-2-(3-Phenylcarbonyl-3-methyl-1-ureido)-2-(3,4-dihydroxyphenyl)]acetamidobisnor- penicillansäure;
6,ß-[D-2-[3-(4-Chlorophenylcarbonyl)-3-methyl-1-ureido]-2-(3,4-dihydroxyphenyl)]acetamidobisnor- penicillansäure oder pharmazeutisch verträgliche Salze oder in vivo hydrolysierbare Ester davon.
7. Ein Verfahren zur Herstellung einer Verbindung wie in Anspruch 1 beansprucht, welches Verfahren umfaßt:
A) die Umsetzung einer Verbindung der Formel (III):
Figure imgb0020
in welcher R wie in Anspruch 1 definiert ist, die a-Aminogruppe gegebenenfalls durch eine Gruppe substituiert ist, welche eine Acylierungsreaktion zuläßt, und R" Wasserstoff oder eine Carboxyl-Hemmgruppe bedeutet, mit einem N-acylieren- den Derivat einer Säure der Formel (IV):
Figure imgb0021
in welcher R1 und R2 wie in Anspruch 1 definiert sind und jede reaktive Gruppe geschützt sein kann;
B) die Umsetzung einer Verbindung der Formel (V):
Figure imgb0022
in welcher die Aminogruppe gegebenenfalls substituiert ist durch eine Gruppe, welche eine Acylierung zuläßt, und R" wie in bezug auf Formel (III) definiert ist, mit einem N-acylierenden Derivat einer Säure der Formel (VI):
Figure imgb0023
in welcher R, R1 und R2 wie in bezug auf Formel (I) definiert sind und alle enthaltenen reaktiven Gruppen geschützt sein können; und anschließend nach den Stufen A) und B), falls notwendig, die Durchführung einer oder mehrerer der folgenden Schritte:
i) Entfernen jeglicher Carboxyl-Hemmgruppen R";
ii) Entfernen jeglicher Schutzgruppen an den Seitenkettengruppen;
iii) Umwandlung des Produkts in ein Salz oder einen in vivo hydrolysierbaren Ester desselben.
8. Eine Zusammensetzung welche eine Verbindung wie in Aneinem der Ansprüche 1 bis 6 beansprucht zusammen mit einem pharmazeutisch verträglichen Träger oder Arzneimittelträger enthält.
9. Eine Zusammensetzung wie in Anspruch 8 beansprucht, welche zusätzlich eine β-Lactamase-Hemmsubstanz enthält.
10. Eine Verbindung wie in einem der Ansprüche 1 bis 6 beansprucht, zur Verwendung bei der Behandlung von antibakteriellen Infektionen bei Mensch und Tier.
EP83302349A 1982-04-29 1983-04-26 Beta-Lactam-Antibiotika Expired EP0093564B1 (de)

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EP (1) EP0093564B1 (de)
JP (1) JPS58203996A (de)
AU (1) AU1398183A (de)
DE (1) DE3372208D1 (de)
ES (2) ES521933A0 (de)
ZA (1) ZA832964B (de)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0131174B1 (de) * 1983-07-07 1989-09-13 Beecham Group Plc Substituierte Phenylglycin-Derivate von Beta-Lactam-Antibiotika
CA2570213C (en) * 2004-07-02 2014-02-18 The Walter And Eliza Hall Institute Of Medical Research Alpha-helical mimetics

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0006532A1 (de) * 1978-06-28 1980-01-09 Dr. Karl Thomae GmbH Neue Lactame, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende Arzneimittel

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Publication number Priority date Publication date Assignee Title
US3487074A (en) * 1966-01-14 1969-12-30 Bristol Myers Co Derivatives of 6-amino-3-penamylcarboxylic acid and 7-amino-2,2-dimethyl-cephalosporanic acid
US4229348A (en) * 1978-05-26 1980-10-21 Chugai Seiyaku Kabushiki Kaisha Penicillanic acid derivatives
US4189482A (en) * 1978-10-12 1980-02-19 E. R. Squibb & Sons, Inc. Penicillins having an imino substituted piperazindioncarbonylamino acyl sidechain
US4206116A (en) * 1978-10-16 1980-06-03 Bristol-Myers Company Novel penicillins
ZA813610B (en) * 1980-06-06 1982-06-30 Beecham Group Plc Penicillin derivatives,processes for their preparation and compositions containing them
NZ197416A (en) * 1980-06-26 1983-11-18 Beecham Group Ltd Penicillin derivatives and pharmaceutical compositions

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0006532A1 (de) * 1978-06-28 1980-01-09 Dr. Karl Thomae GmbH Neue Lactame, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende Arzneimittel

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DE3372208D1 (en) 1987-07-30
AU1398183A (en) 1983-11-03
ES528490A0 (es) 1985-06-16
ES8604232A1 (es) 1985-06-16
ES8406076A1 (es) 1984-07-01
US4540688A (en) 1985-09-10
ES521933A0 (es) 1984-07-01
JPS58203996A (ja) 1983-11-28
EP0093564A1 (de) 1983-11-09

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